Observation of σ-pore currents in mutant hKv1.2_V370C potassium channels

Current through the sigma-pore was first detected in hKv1.3_V388C channels, where the V388C mutation in hKv1.3 channels opened a new pathway (sigma-pore) behind the central alpha-pore. Typical for this mutant channel was inward current at potentials more negative than -100 mV when the central alpha-pore was closed. The alpha-pore blockers such as TEA(+) and peptide toxins (CTX, MTX) could not reduce current through the sigma-pore of hKv1.3_V388C channels. This new pathway would proceed in parallel to the alpha-pore in the S6-S6 interface gap. To see whether this phenomenon is restricted to hKv1.3 channels we mutated hKv1.2 at the homologue position (hKv1.2_V370C). By overexpression of hKv1.2_V370C mutant channels in COS-7 cells we could show typical sigma-currents. The electrophysiological properties of the sigma-pore in hKv1.3_V388C and hKv1.2_V370C mutant channels were similar. The sigma-pore of hKv1.2_V370C channels was most permeable to Na+ and Li+ whereas Cl- and protons did not influence current through the sigma-pore. Tetraethylammonium (TEA(+)), charybdotoxin (CTX) and maurotoxin (MTX), known alpha-pore blockers, could not reduce current through the sigma-pore of hKv1.2_V370C channels. Taken together we conclude that the observation of sigma-pore currents is not restricted to Kv1.3 potassium channels but can also be observed in a closely related potassium channel. This finding could have implications in the treatment of different ion channel diseases linked to mutations of the respective channels in regions close to homologue position investigated by us.